This Is MS Multiple Sclerosis Community: Knowledge & Support

Welcome to the world's leading forum on Multiple Sclerosis research, support, and knowledge. For over 10 years, This is MS has provided an unbiased community dedicated to Multiple Sclerosis patients, caregivers, and affected loved ones.

October 14, 2009 --Although the human genome sequence faithfully lists (almost) every single DNA base of the roughly 3 billion bases that make up a human genome, it doesn't tell biologists much about how its function is regulated. Now, researchers at the Salk Institute provide the first detailed map of the human epigenome, the layer of genetic control beyond the regulation inherent in the sequence of the genes themselves.

"In the past we've been limited to viewing small snippets of the epigenome," says senior author Joseph Ecker, Ph.D., professor and director of the Genomic Analysis Laboratory at the Salk Institute and a member of the San Diego Epigenome Center. "Being able to study the epigenome in its entirety will lead to a better understanding of how genome function is regulated in health and disease but also how gene expression is influenced by diet and the environment."

Their study, published in the Oct. 14, 2009 advance online edition of the journal Nature, compared the epigenomes of human embryonic stem cells and differentiated connective cells from the lung called fibroblasts, revealing a highly dynamic, yet tightly controlled, landscape of chemical signposts known as methyl-groups. The head-to-head comparison brought to light a novel DNA methylation pattern unique to stem cells, which may explain how stem cells establish and maintain their pluripotent state, the researchers say.

The emergence of epigenetics has already changed the way researchers think about how disease arises and how physicians treat it. Epigenetic changes play a crucial role in the development of cancer and some drugs that directly interact with the epigenome have been approved for the treatment of lymphoma and lung cancer and are now tested against a number of other cancer types. "Unless we know how these drugs affect the entire epigenome, we don't really understand their full mechanism of action," says Ecker.

Recognizing the central role of the epigenome in many areas of biology and medicine the National Institutes of Health launched a five-year Roadmap Epigenomics Program in 2008. The San Diego Epigenome Center, headed by Bing Ren, Ph.D., Professor of Cellular and Molecular Medicine at the University of California, San Diego School of Medicine and head of the Laboratory of Gene Regulation at the Ludwig Institute for Cancer Research, is an integral part of the five-year, $190 million push to accelerate research into modifications that alter genetic behavior across the human genome.

The current study, to which Ren and additional members of the Center located at the University of Wisconsin and the Morgridge Institute for Research in Madison, Wisconsin, also contributed, is not only the first complete high-resolution map of an epigenome superimposed on the human genome, but also the first study to be published as a direct result of the Roadmap Epigenomics Program.

"This paper exemplifies the goals of the NIH Roadmap for Medical Research's Epigenomics Program," said Linda Birnbaum, Ph.D., director of the National Institute of Environmental Health Sciences, one of the NIH institutes funding this program. "The science has matured to a point that we can now map the epigenome of a cell. This paper documents the first complete mapping of the methylome, a subset of the entire epigenome, of 2 types of human cells - an embryonic stem cell and a human fibroblast line. This will help us better understand how a diseased cell differs from a normal cell, which will enhance our understanding of the pathways of various diseases."

Epigenetic signals can tinker with genetic information in at least two ways: One targets histones, the "spools" around which DNA winds and which control access to DNA. The other is DNA methylation, a chemical modification of one letter, C (cytosine), of the four letters (A, G, C, and T) that comprise our DNA. In the last couple of years, Ecker's laboratory started to zoom in on genomic methylation patterns, which are essential for normal development and are associated with a number of key cellular processes, including carcinogenesis.

Perfecting the technique in Arabidopsis thaliana, a plant whose genome is 25 times smaller than the human genome, Ryan Lister, Ph.D., a postdoctoral researcher in Ecker's lab and co-first author on the current study, developed an ultra high-throughput methodology to precisely determine whether each C in the genome is methylated or not, and layer the resulting epigenomic map upon the exact genome it regulates.

He then put the brand new technology to work to map the epigenomes of differentiated fibroblast cells and human embryonic stem cells (hESCs.) "We wanted to know how the epigenome of a differentiated cell that's programmed to perform a specific job differs from the epigenome of a pluripotent stem cell, that has the potential to turn into any other cell type," Lister says.

Just as expected, in fibroblast cells the majority of Cs followed by a G carried a methyl-group, a pattern often referred to as CG-methylation. But much to the Salk researchers' surprise, in embryonic stem cells about a quarter of all methylation events occurred in a different context.

"Non-CG methylation is not completely unheard of -- people have seen it in dribs and drabs, even in stem cells. But nobody expected that it would be so extensive," says postdoctoral researcher and co-first author Mattia Pelizzola, who along with Lister undertook the extensive task of extracting and analyzing the epigenome data from these vast sequence datasets. "The whole field had been focused on CG methylation, and non-CG methylation was often considered a technical artifact."

To confirm their finding, the authors then targeted several regions in a second hESC line, as well as in fibroblast cells that had been reprogrammed into so called induced pluripotent stem (iPS) cells. "They both had the same high level of non-CG methylation, which was lost when we forced them to differentiate," says Pelizzola.

Being able to create high resolutions maps of the human epigenome, Ecker's group will now begin to examine how it changes during normal development as well as examining a variety of disease states. "For the first time, we will be able to see the fine details of how DNA methylation changes in stem cells and other cells as they grow and develop into new cell types," he says. "We believe this knowledge will be extremely valuable for understanding diseases such as cancer and possibly even mental disorders. Right now we just don't know how the epigenome changes during the aging process or how the epigenome is impacted by our environment or diet."

Advertisement

Genomes of identical twins reveal epigenetic changes that may play role in lupus

December 21, 2009 -- Identical twins look the same and are nearly genetically identical, but environmental factors and the resulting cellular changes could cause disease in one sibling and not the other. In a study published online in Genome Research, scientists have studied twins discordant for the autoimmune disease lupus, mapping DNA modifications across the genome and shedding light on epigenetic changes that may play a role in the disease.

Because the genetic makeup of monozygotic twins (commonly known as identical twins) is nearly identical, phenotypic traits and heritable diseases are often concordant, manifesting in both siblings. However, some phenotypes and diseases such as autoimmune disease can arise in only one sibling, suggesting other factors such as environment likely play a role in determining phenotypic differences.

Epigenetic modifications, cellular changes that can influence expression of genes, are now widely recognized to influence phenotype and frequently occur in disease. Furthermore, environmental factors such as diet and chemical exposure can change the epigenetic status of genes. Recent research has identified epigenetic modifications at several aberrantly regulated genes in autoimmune diseases such as systemic lupus erythematosus (SLE), and other studies have suggested that epigenetic differences are associated with phenotypic discordance between identical twins.

We are trying to form an international consortium on Epigenetics & Autoimmunity. Our initial meeting was in Brest France in October and we are trying to find a sponsor (so far no luck) to fund another satellite session on Epigenetics & Autoimmunity at the Autoimmunity Congress in Ljubljana, Slovenia in May 2010. I am going to that meeting whether or not there is a satellite session but I really hope the session happens. Otherwise there may only be a few epigenetics posters scattered throughout the other topics. Epigenetics & Autoimmunity is a timely topic and so it would be good to give it more visibility at this meeting where there is expected to be 2,000 immunology researchers attending. This is a meeting that occurs only about every three years so it is an important opportunity.
Keep thinking Epigenetics. And pray that we can find a sponsor so we can get the researchers together.

Wesley

As far as twin studies, the same author has another article out recently on twins in Clinical Reviews in Allergy and Immunology (online first version):
Epigenetics Lessons from Twins: Prospects for Autoimmune Disease

Abstract The existence of phenotypic differences between monozygotic (MZ) twins is a prime case where the relationship between genetic determinants and environmental factors is illustrated. Although virtually identical from a genetic point of view, MZ twins show a variable degree of discordance with respect to different features including susceptibility to disease. Discordance has frequently been interpreted in terms of the impact of the environment with genetics. In this sense, accumulated evidence supports the notion that environmental factors can have a long-term effect on epigenetic profiles and influence the susceptibility to disease. In relation with autoimmune diseases, the identification of DNA methylation changes in individuals who develop the disease, and the influence of inhibitors of DNA methyltransferases and histone modification enzymes in the development of autoimmunity are attracting the attention of researchers in the epigenetics field. In this context, the study of discordant MZ twins constitutes an attractive model to further investigate the epigenetic mechanisms involved in their development as well as to dissect the contribution of environmental traits. The implications of novel strategies to map epigenetic profiles and how the use of MZ twins can contribute to dissect the epigenetic component of autoimmune disease are discussed.

Wesley, thanks for posting the abstract. I think I like this Ballestar character. Good luck finding funding for your satellite session. It sounds like a valuable consortium you're forming. If I run into any filthy rich philanthropists, I'll send them your way.

As squiffy posted already, it's not epigenetics after all! Of course nobody knows what is causing MS yet, but this study suggests some interesting possibilities. Aside from possibly increasing the prominence of environmental factors, the researchers also,

noticed a surprising difference between the genomes of twins that was not correlated to MS. They discovered an imbalance in which one copy of a gene is expressed at higher levels than the other copy. This phenomenon, known as allelic imbalance, causes differences in the levels of mRNA expression.

"We found many instances where an allelic imbalance was larger in one twin than in the other, or where the imbalance was flipped between the two alleles," said Baranzini. Those differences were unexpected and are likely to be of interest in future studies of twins, whether the focus is on MS or other diseases, he said.

There is no such thing as identical where twins are concernedOctober 14, 2011 - Identical twins have identical genomes, but that is where it stops. There are subtle differences in their personalities, how they look, how they act and in their susceptibility to disease. How can this be?

It all depends on how the “epigenome” is modified by the environment, say scientists from Sydney’s Garvan Institute of Medical Research and Queensland Medical Research Institute, who have just completed an 8-year study involving 512 adolescent twins (128 identical twin pairs, as well as 128 non-identical twin pairs), with an average age of 14.15 years.

More specifically, it depends on exactly how particular parts of the genome are affected by ‘methylation’, or the attachment of hydrocarbon molecules - ‘methyl groups’, that literally change the voice of the genome, silencing some genes and amplifying others.

Garvan epigeneticists Dr Marcel Coolen and Professor Susan Clark focused on the methylation profiles of a group of ‘imprinted’ genes that are important in the control of growth during early development. They found differences in the methylation profiles of these imprinted genes, even in genetically identical twins. It is these changes, they say, that probably give rise to differences we observe in identical twins. Their findings are published in the International journal PLoS One, now online.

“The aim of our study was to understand what role genetics plays in determining who we are, versus the role of environmental factors,” said project leader Professor Susan Clark.

“Our findings support the hypothesis that changes in methylation reflect the interplay between the environment and genetics.”

“We showed that methylation patterns are exquisitely inherited, and so the methylation patterns of identical twins are still very similar to each other. This demonstrated that the DNA sequence does instruct the methylation pattern. When that methylation pattern changes, however, it gives rise to potential changes in phenotype, or who we are.”

“This is one of the largest studies ever undertaken of this sort, and these are challenging studies, so having proof of principle is important.”

“We now have evidence that changes in methylation patterns occur in genetically identical people and therefore these changes can potentially change disease susceptibility. The next step will be to examine twins that are discordant for a particular disease – such as Type 2 diabetes. In those cases, we will be looking for discordance in methylation of the key genes.”

Who is online

This site does not offer, or claim to offer, medical, legal, or professional advice.
All treatment decisions should always be made with the full knowledge of your physicians.
This is MS does not create, endorse, or republish any content.
All postings are the responsibility of the poster. All logos and trademarks in this site are property of their respective owners. All users must respect our rules for intellectual property rights.